Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening.
Small molecule inhibitors of SHP2 tyrosine phosphatase discovered by virtual screening.
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DOI：
10.1016/j.bmcl.2011.05.078
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发表时间：
2011-07-15
影响因子：
2.7
通讯作者：
Zhang, Zhong-Yin
中科院分区：
文献类型：
--
作者：
Yu, Zhi-Hong;Chen, Lan;Wu, Li;Liu, Sijiu;Wang, Lina;Zhang, Zhong-Yin
关键词：
SHP2, encoded by PTPN11, is a non-receptor protein tyrosine phosphatase (PTP) containing two tandem Src homology-2 (SH2) domains. It is expressed ubiquitously and plays critical roles in growth factor mediated processes, primarily by promoting the activation of the RAS/ERK signaling pathway. Genetic and biochemical studies have identified SHP2 as the first bona fide oncoprotein in the PTP superfamily, and a promising target for anti-cancer and anti-leukemia therapy. Here, we report a structure-based approach to identify SHP2 inhibitors with a novel scaffold. Through sequential virtual screenings and in vitro inhibition assays, a reversible competitive SHP2 inhibitor (C21) was identified. C21 is structurally distinct from all known SHP2 inhibitors. Combining molecular dynamics simulation and binding free energy calculation, a most likely binding mode of C21 with SHP2 is proposed, and further validated by site-directed mutagenesis and structure-activity relationship studies. This binding mode is consistent with the observed potency and specificity of C21, and reveals the molecular determinants for further optimization based on the new scaffold.
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影响因子：
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作者：
Geronikaki, A.;Eleftheriou, P.;Saxena, A. K.
通讯作者：
Saxena, A. K.
影响因子：
8
作者：
Miyamoto, D.;Miyamoto, M.;Hatakeyama, M.
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Hatakeyama, M.
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11.2
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Bentires-Alj, M;Paez, JG;Neel, BG
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Neel, BG
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64.5
作者：
Barr AJ;Ugochukwu E;Lee WH;King ON;Filippakopoulos P;Alfano I;Savitsky P;Burgess-Brown NA;Müller S;Knapp S
通讯作者：
Knapp S
影响因子：
4.5
作者：
Lang, P. Therese;Brozell, Scott R.;Kuntz, Irwin D.
通讯作者：
Kuntz, Irwin D.